茵陈蒿汤及其拆方治疗非酒精性脂肪性肝炎的实验研究
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摘要
本文通过文献综述、动物实验研究两方面阐述了现代医学和中医药对非酒精性脂肪性肝炎(NASH)的认识、治疗及实验研究现状,探讨茵陈蒿汤治疗NASH的疗效和作用机制,以探索古方新用,提升经方在该领域的研究价值和临床治疗水平。
1文献综述
通过近10年的国内外文献资料分析,探讨归纳了NASH现代医学的病因、发病机制、治疗研究近况及中医学的NASH病因病机、体质学、证候学、治疗研究的进展情况。
2茵陈蒿汤对MCD小鼠模型NASH的研究
目的
探讨茵陈蒿汤治疗MCD小鼠模型NASH的疗效。
方法
MCD饲料喂养雄性C56BL/6小鼠2周建立NASH小鼠模型,造模成功后,各治疗组分别给予茵陈蒿汤高、中(临床常规剂量)、低剂量灌胃干预2周,空白组和模型组给予蒸馏水干预,治疗结束后处死各组小鼠,观察各组小鼠的肝组织病理学改变,检测肝功能、血脂、肝组织SOD、GSH-PX活性、MDA及肝脂含量。
结果
(1)一般情况及病理形态学：模型组小鼠较空白组NAS病理评分显著升高,体重降低、肝指数升高；茵陈蒿汤高、中剂量组能显著降低模型的肝指数,各剂量组均能明显降低模型组脂肪变性、小叶内炎症、气球样变评分。
(2)肝脏酶学：模型组小鼠肝酶学水平较空白组显著升高,茵陈蒿汤中剂量组能显著降低小鼠ALT水平,茵陈蒿汤高、低剂量组对肝酶学水平无显著影响。
(3)血脂及肝脂：模型组血清TC、TG、HDL-C含量较窄白组降低,LDL-C、肝TG含量显著升高,茵陈蒿汤高、中剂量组能显著降低血清TC,TG, LDL-C、及肝TG含量；低剂量组能显著降低TC、LDL-C及肝TG含量,各剂量组对HDL-C水平无显著影响。
(4)抗氧化及改善脂质过氧化：模型组肝组织GSH-PX、SOD含量较空白组显著降低,MDA升高；各剂量组均能降低模型肝内MDA含量,对肝内SOD、GSH-PX水平无显著影响。
结论
茵陈蒿汤配方颗粒剂型临床常规剂量能显著改善MCD小鼠NASH模型的肝组织病理、改善肝细胞脂肪变性,通过促进小鼠模型的肝脂血脂代谢、抑制脂质过氧化反应,减轻肝细胞损伤而降低ALT,对增强抗氧化能力作用不显著。茵陈蒿汤的临床常规剂量疗效优于高剂量,高剂量又优于低剂量。
3茵陈蒿汤对HFD大鼠模型NASH的研究
目的
探讨茵陈蒿汤治疗HFD大鼠模型NASH的疗效及对胰岛素抵抗的调控作用。
方法
高脂饲料喂养SD雄性大鼠8周建立NASH大鼠模型,造模成功后,各治疗组分别给予茵陈蒿汤高、低剂量(临床常规剂量)及复方益肝灵灌胃治疗4周,自然恢复组予基础饲料。治疗结束后所有大鼠取材,观察各组大鼠的肝组织病理学改变,检测肝功能、血脂、肝脂、血糖、血清胰岛素含量及抗氧化指标,计算HOMA-IR,RT-PCR法检测肝组织DGAT-2、PKC-ε、IRS-1、TNF-α mRNA的表达水平。
结果
(1)病理：茵陈蒿汤低剂量组和自然恢复组能显著、全面改善模型肝组织脂肪变性、气球样变及炎症的病理表现,茵陈蒿汤高剂量组、复方益肝灵组能显著改善炎症及气球样变,降低NAS评分,而对脂肪变性的评分降低不显著。
(2)肝脏酶学：茵陈蒿汤高剂量组显著升高模型ALT、AST水平,复方益肝灵组显著升高AST水平,而茵陈蒿汤低剂量组能一定程度降低ALT、AST水平,自然恢复组对ALT、AST无显著调节作用。
(3)血脂及肝脂：复方益肝灵组、茵陈蒿汤低剂量组均能显著降低血清TC、TG. LDL-C水平,高剂量组能降低血清TG含量,自然恢复组能降低血清TG,LDL-C含量,但三个药物治疗组对HDL-C的水平均无显著影响,自然恢复组对升高HDL-C水平具有显著调节。茵陈蒿汤低剂量组及自然恢复组能显著降低模型肝组织FFA、DAG、TG含量,茵陈蒿汤高剂量组、复方益肝灵组能显著减少肝组织FFA、DAG含量,对降低TG作用不显著。茵陈蒿汤低剂量在调节脂质代谢方面的疗效优于高剂量与复方益肝灵片,在调节血脂方面,复方益肝灵片优于高剂量,而在调节肝脂方面,两者作用相当。
(4)血糖、胰岛素及外周胰岛素抵抗：茵陈蒿汤高、低剂量组及复方益肝灵组能显著降低FBG、FINS含量及HOMA-IR,各组间无显著差异。自然恢复组FINS水平及HOMA-IR有下调趋势,FBG水平升高有升高趋势,但无显著意义。
(5)抗氧化及改善脂质过氧化：茵陈蒿汤低剂量组能显著降低血清、肝脏MDA含量,升高血清GSH-PX水平,高剂量组能显著降低血清MDA含量,升高血清GSH-PX水平,茵陈蒿汤两个剂量组对肝内GSH-PX含量无显著影响。复方益肝灵组能显著降低血清及肝内MDA含量,对血清及肝脏GSH-PX有升高趋势,但无显著差异。自然恢复组既能显著降低血清、肝内MDA含量,也能升高血清、肝内GSH-PX水平,各组对血清及肝内SOD水平均无显著影响。茵陈蒿汤低剂量对脂质过氧化的整体作用优于高剂量。在增强外周抗氧化能力方面,茵陈蒿汤优于复方益肝灵片,在增强肝脏抗氧化能力方面,复方益肝灵片对模型虽无显著改善,但其作用优于茵陈蒿汤。
(6)肝脏胰岛素抵抗及炎症：茵陈蒿汤低剂量组能显著降低)GAT-2、PKC-ε、TNF-a mRNA表达水平,升高IRS-1mRNA表达水平,高剂量组及复方益肝灵组能显著降低PKC-ε、TNF-α mRNA表达水平,升高IRS-1mRNA表达水平,对DGAT-2表达有抑制作用,但无显著意义。
结论
(1)茵陈蒿汤能够针对NASH发病的“二次打击”机制起效。针对第一次打击的IR和脂质代谢紊乱环节,减少肝内积聚的过量脂质,促进血脂代谢,改善肝细胞脂肪变性状态,并调节血糖、胰岛素的分泌利用,改善外周IR。针对第二次打击氧应激和脂质过氧化的环节,增强外周抗氧化能力、清除自由基代谢产物,抑制脂质过氧化和炎症反应,恢复氧化系统的失衡状态。茵陈蒿汤常规剂量的作用优于高剂量。在减轻肝脂积聚、增强外周抗氧化能力方面,常规剂量优于复方益肝灵片,复方益肝灵片在增强肝脏抗氧化能力方面优于茵陈蒿汤常规剂量。
(2)茵陈蒿汤高剂量可能由于过量使用对模型肝脏存在一定的毒副作用,复方益肝灵片也对模型肝脏产生了一定的毒副作用,但其具体原因尚不能定论。高剂量与复方益肝灵片作用相当,复方益肝灵片在增强肝脏抗氧化能力方面优于茵陈蒿汤高剂量。
(3)茵陈蒿汤调控NASH大鼠模型肝脏IR的作用机制,部分可能为通过作用于DAG-PKCε信号通路异常的相关因子和炎症因子起效。
(4)模型大鼠在无药物干预的情况下,在血脂、肝脂代谢、脂质过氧化程度的改善和外周抗氧化能力增强方面恢复较好,而在肝细胞的修复、葡萄糖的摄取利用、胰岛素的分泌调节方面短期不能自行恢复而需药物干预。
4茵陈蒿汤拆方对HFD大鼠模型的正交研究
目的
从拆方的角度出发研究茵陈蒿汤对NASH的作用机制,探讨方中各药物及组合对NASH的作用疗效差异,以认识各药物与NASH的相关性,明确药物间的组合是否具有交互作用。
方法
采用正交设计法,对茵陈蒿汤的组成药物进行3因素、2水平的交互研究,运用正交表L8(2’)将大鼠分为8组,高脂饲料喂养SD雄性大鼠8周建立NASH大鼠模型,造模成功后,各治疗组分别给予茵陈、栀子、大黄、茵陈栀子、茵陈大黄、栀子大黄、茵陈蒿汤灌胃治疗4周,治疗结束后所有大鼠取材,观察各组大鼠的肝组织病理学改变,检测肝功能、血脂、肝脂、血糖、血清胰岛素含量及抗氧化指标,RT-PCR法检测肝组织TNF-α mRNA的表达水平。
结果
(1)一般情况及病理形态学：模型组NAS病理评分、体重、肝指数较空白组明显升高；栀黄组体重、茵陈蒿汤组肝指数有降低趋势,但无显著差异,其余各治疗组体重及肝指数均有显著降低；各治疗组脂肪变性、小叶内炎症、气球样变评分均显著下降,各治疗组之间无显著差异。
(2)肝脏酶学：大黄组、茵陈组、栀子组能显著降低ALT水平(P=0.043,0.047,0.042)；大黄组能显著降低AST水平(P=0.039),茵陈组、栀子组作用不显著(P=0.054,0.088)。对三种药物各自用药与不用药时的疗效差异进行比较,各因素对ALT的效应程度为栀子>大黄>茵陈,对AST为茵陈>大黄>栀子,且均以用药水平为优；茵黄组对ALT、AST存在交互作用(P=0.039,0.024),栀黄组、茵栀组对AST存在交互作用(P=0.021,0.046),对ALT不存在交互作用(P=0.057,0.055)。
(3)血糖、胰岛素：大黄组、茵陈组能显著降低FINS水平(P=0.032,0.049),栀子组作用不显著(P=0.213)；大黄组、茵陈组能显著降低FBG水平(P=0.049,0.040),栀子组作用不显著(P=0.075)。各因素对FINS的效应程度为茵陈>栀子>大黄,对FBG为大黄>茵陈>栀子,均以用药水平为优；茵黄组、栀黄组对FINS(P=0.011,0.023)、FBG存在交互作用(P=0.018,0.046),茵栀组对FBG存在交互作用(P=0.031),对FINS不存在交互作用(P=0.134)。
(4)血脂及肝脂：大黄组、茵陈组、栀子组能显著降低TC水平(P=0.020,0.022,0.020)；大黄组、栀子组能显著降低血清TG(P=0.044,0.039)、LDL-C(P=0.042,0.013)、肝组织TG(P=0.012,0.035)含量,茵陈组作用不显著(P=0.288,0.156,0.110)；大黄组能显著升高HDL-C水平(P=0.045),茵陈组、栀子组作用不显著(P=0.056,0.081)；各因素对血清TG、TC、肝脏TG的效应程度均为大黄>栀子>茵陈,均以用药水平为优；对LDL-C为栀子>大黄=茵陈,栀子、大黄以用药水平为优,茵陈以不用药水平为优；对HDL-C为大黄=茵陈>栀子,大黄、茵陈以用药水平为优,栀子以不用药水平为优；茵黄组、栀黄组、茵栀组对血清TC(P=0.021,0.045,0.021)、TG(P=0.045,0.025,0.026)、LDL-C(P=0.002,0.003,0.002)、肝组织TG(P=0.016,0.027,0.037)存在交互作用,对HDL-C不存在交互作用(P=0.063,0.058,0.157)。
(5)抗氧化及改善脂质过氧化：大黄组、茵陈组、栀子组能显著降低血清MDA(P=0.009,0.01,0.006)及肝组织MDA含量(P=0.008,0.009,0.013),各因素对血清MDA的效应程度为大黄>茵陈>栀子,对肝组织MDA为茵陈>大黄>栀子,均以用药水平为优,三者以栀子对MDA含量影响效应程度最小；茵黄组、栀黄组、茵栀组对血清MDA(P=0.047,0.008,0.005)及肝组织MDA(P=0.016,0.006,0.047)存在交互作用；大黄组、茵陈组、栀子组能显著升高血清GSH-PX水平(P=0.017,0.014,0.009),茵陈组、栀子组能显著升高肝组织GSH-PX含量(P=0.034,0.014),大黄组作用不显著(P=0.052),各因素对血清GSH-PX的效应程度为栀子>大黄>茵陈,均以用药水平为优；对肝组织GSH-PX为栀子>茵陈>大黄,栀子、茵陈以用药水平为优,大黄以不用药水平为优,三者中以栀子对GSH-PX含量的影响程度最大；茵黄组、茵栀组对血清GSH-PX存在交互作用(P=0.045,0.008),栀黄组不存在交互作用(P=0.101)；茵黄组对肝组织GSH-PX存在交互作用(P=0.029),茵栀组、栀黄组不存在交互作用(P=0.063,0.072)。
(6)炎症：大黄组、茵陈组、栀子组能显著降低血清TNF-α水平(P=0.021,0.048,0.014),大黄组、栀子组能显著降低肝组织TNF-α mRNA表达水平(P=0.049,0.036),茵陈组作用不显著(P=0.100),各因素对血清TNF-α的效应程度为栀子=大黄>茵陈,对TNF-α mRNA为栀子>大黄>茵陈,均以用药水平为优,三者以栀子对TNF-α影响程度最大,茵陈最小；茵黄组、栀黄组、茵栀组对血清TNF-α存在交互作用(P=0.048,0.022,0.011),茵栀组对肝组织TNF-a mRNA表达具交互作用(P=0.040),茵黄组、栀黄组未见交互(P=0.066,0.322)。
结论
(1)大黄、茵陈、栀子单独使用时对大鼠NASH模型的脂代谢紊乱、胰岛素效应降低、脂质过氧化、炎症等方面即存在显著疗效,其作用多有相似又各有侧重,药物间的作用对治疗NASH具有互补性,大黄保肝降酶及调节血脂的作用最佳,茵陈与栀子对增强机体抗氧化能力的作用优于大黄,大黄、茵陈与栀子在调节模型血糖、胰岛素水平方面的作用具有互补性。大黄较茵陈、栀子对该模型可能具有更全面的治疗作用。
(2)三种药物的组合对NASH的多个方面具有协同交互作用,各组合间的作用对治疗NASH具有互补性,茵陈与大黄能协同增强模型的肝脏抗氧化能力,优于其他组合；茵陈与栀子能协同抑制模型肝脏炎症,优于其他组合；栀子与大黄在增强机体抗氧化能力方面无显著交互作用。
(3)根据上述研究结果综合分析,推测茵陈蒿汤全方对HFD大鼠NASH模型在降脂方面作用可能不及大黄,在保肝、抑炎、抑制脂质过氧化调节血糖与胰岛素的水平方面,可能较其他单药或组合更佳,对肝脏抗氧化能力的调节作用是否优于各组合尚需研究证实。
(4)茵陈蒿汤在临床中使用的常规剂量可能较高、低剂量更为安全有效,本研究中,传统水煎剂较配方颗粒剂型表现出更佳的疗效趋势。
Comprehensive learning of non-alcoholic steatohepatitis(NASH) in both modern medicine and traditional chinese medicine (TCM)is demonstrated through literature review,and animal experimental study in this paper. Efficacy and mechanism of Yinchenhao Decoction is explored in the animal experimental study.The research provided a basis to further reveal the mechanism of Yinchenhao Decoction and to explore new Cuban side to enhance by the side of the value of academic research in the field and clinical therapeutic levels.
1Literature review
Through literature analysis in recent10years both at home and abroad, the etiology,pathogenesis,and treatment of modern medicine, also etiology and pathogenesis, syndrome differentiation, physical sciencetreatment progress of TCM have been review.
2Effects of Yinchenhao Decoction on mice with NASH on MCD diet
Objective
To investigate the efficacy of Yinchenhao Decoction(YCHD) on mice with non-alcoholic steatohepatitis (NASH) on MCD diet.
Method
The C57BL/6mice was fed with MCD diet for2weeks to make NASH mice model. After modeling, the treatment group were intervened by YCHD high, middle (conventional dosage), low dose for4weeks. Then the change of serum transaminase, serum lipid, liver lipid, Lipid peroxidation indexes and the liver pathology had been detected to observe the efficacy.
Outcome
(1) General condition and pathomorphology:The hepatic steatosis and inflammation,also liver index were increased, body weight was reduced in model group, but improved in the treatment group compared with model group. NAS score was reduced significantly at the same time.And there was no significant difference between the all treatment group. Liver index was reduced significantly in the high and middle dose groups of YCHD group.
(2) Serum transaminase:Compared with blank control group, the serum ALT, AST in model group were obviously increased. The serum ALT decreased in YCHD middle dose group, and there was no signicficant difference in improving liver function them. The indexes had no signicf icant change in high and low dose groups of YCHD.
(3) Lipid:Serum TC, TG, HDL-C was reduced, LDL-C and TG in liver was increased in the model compared with blank control group. The high and middle dose groups of YCHD could decrease serum TC, TG, LDL and liver TG significantly, the low dose of YCHD could decrease serum TC, LDL and liver TG. There was no signicficant change in serum HDL of all groups.
(4) Lipid peroxidation indexes:In model group, the MDA content in liver were increased, the GSH-PX and SOD was decreased compared with the blank control group. In treatment groups, the MDA were decreased significantly. As the GSH-PX and SOD, there was no significant difference among all groups.
Conclusion
The three dose of YCHD could improve the liver pathological change, decrease liver lipid and MDA level significantly. The high and middle dose was good at reducing liver index and blood lipid, which was better than the low dose at blood lipid. Only the middle dose could reduce the serum ALT. Overall, the efficacy of conventional dose was the best among them, and the high dose is better than the low.
3Research of efficacy and therapeutic mechanism of YCHD to NASH for rat fed on high fat diet
Objective
To investigate the efficacy and therapeutic mechanism on regulating insulin resistance of YCHD on rat with NASH on high fat diet.
Methods
NASH model in SD rats was established by feeding high fat diet for8weeks, After modeling, the treatment and control group were intervened by YCHD high, low(conventional dose) dose and compound yiganling for4weeks, natural recovery group was restored to normal diet. Then the change of serum transaminase, serum lipid,fas ting blood glucose, fasting insulin,liver lipid, lipid peroxidation indexes,the liver pathology and expression levels of DGAT-2、PKC-ε、INS-1、TNF-α、mRNA of the liver had been detected to observe the efficacy and mechanism.
Outcome
(1) Pathomorphology change:After treatment, the steatosis, lobular inflammation, ballooning and total scores all decreased by the low dose of YCHD and natural recovery group s ignif icant ly. The high dose of YCHD and control group improved the lobular inflammation and ballooning.
(2) Serum transaminase:The serum transaminase was increased in YCHD high dose group,and the serum AST increased in control group. The low dose of YCHD reduced the serum transaminase but there was no signicficant change.
(3) Lipid:Serum TC, TG, LDL-C was reduced in the low dose of YCHD and control group, TG reduced in the high dose, TG reduced in the natural recovery group. There was no signicficant change on HDL-C in the treatment groups,while increased in the natural recovery group. ALL groups could reduced FFA contents in the liver and there was no signicficant difference between them, the low dose of YCHD could decrease DAG, TG contents in the liver, the high dose and compound yiganling decrease DAG signicficantly.
(4) FBG,FINS and peripheral insulin resistance:The level of FBG and FINS in serum of all treatment groups were significantly lower than those of model group. There was no significant difference among them. ALL groups could reduce the level of HOMA-IR, but there was no significant change.
(5) Lipid peroxidation indexes:The activities of serum GSH-PX and level of serum and1iver MDA were significantly improved in the low dose of YCHD, which was better than that of the high dose and compound yiganling group. GSH-PX in liver had no significant change in all treatment groups. While the natural recovery group could increase GSH-PX in liver also the other lipid peroxidation indexes. There was no significant change on SOD in all groups.
(6) Hepatic insulin resistance and inflammation:The expression of PKC-5and TNF-a in liver was significantly reduced, the expression of IRS-1was increased in all treatment groups.There was no significant difference among them. Meanwhile, the low dose of YCHD could also reduce the expression of Dgat-2in liver, but the level of it had no signif icant change in high dose and yiganling group.
Conclusion
(1) YCHD has good efficacy on NASH rats feeding by high fat diet with pathogenesis of "two-hit" mechanism by improving the steatosis, disorders of glucose and lipid metabolisin, also peripheral insulin resistance. Enhancing antioxidant ability and clearing free radical metabolites to inhibit lipid peroxidation. YCHD conventional dose is better than high dose on rats NASH model. On enhancing the periphery antioxidant capacity and alleviating liver fat accumulation, YCHD conventional dose was better than compound yiganling piece. On enhancing liver antioxidant capacity, compound yiganling tablets was better than YCHD conventional dose.
(2) There might be certain side effects due to excessive use of high dose. The compound yiganling sheet had certain side effects also, but the specific cause could not yet be conclusive. The high dose was quite to compound yiganling piece. On enhancing liver antioxidant capacity, compound yiganling tablets was better than YCHD high dose.
(3) By regulating the related factors and inflammatory factors on signaling pathway of DAG-PKC ε, YCHD could improve he patic insulin resistance. This is part of the mechanism of the regulation of insulin resistance by YCHD.
(4) Rat model in the case of non-pharmacological interventions, had better recovery in blood lipids, liver lipid metabolism, lipid peroxidation degree and the outer periphery of antioxidant capacity, but could not restore itself without a drug intervention in repairing liver cells, uptake and utilization of glucose, regulation of insulin secretion in short-term.
4Research of interaction by disassembling YCHD to NASH for rat fed on high fat diet by orthogonal design
To observe the difference of efficacy of each herb and combinations in YCHD on NASH for the correlation between drugs and NASH, interaction between drugs.
Method
Methods of orthogonal design and disassembling the prescription was taken in this study, three factors and two level are confirmed, according to orthogonal layout L8(2'), rats were divided into8groups and were intervened by corresponding herb and combination for4weeks to observe the pathological changes of hepatic tissue, serum transaminase, serum lipid, fasting blood glucose, fasting insulin,liver lipid, lipid peroxidation indexes, and expression levels of TNF-a in liver.
Outcome
(1) General condition and pathomorphology change:The NAS score, body weight and liver index were increased in model group. Except body weight of YCHD, and liver index of gardenia and rhubarb group,NAS score of steatosis, lobular inflammation, ballooning in other treatment groups was reduced significantly. There was no significant difference among all treatment groups.
(2) Serum transaminase:The level of serum ALT was reduced in gardenia, rhubarb and capllaris group, of serum AST was reduced in rhubarb group significantly. When medication and non-medication, the degree of the affection by all factors on ALT is gardenia> rhubarb>capi1laris, on AST was capillaris>rhubarb>gardenia, and all of the level in medica t ion was better than that in non-medication.There was interaction on ALT, AST in group of capillaris and rhubarb, interaction on AST in rhubarb and gardenia, capillar is and gardenia.
(3) FBG and FINS:Rhubarb group and capillar is group could reduce the level of FINS and FBG significantly. The degree of the affection by all factors on FINS was capillaris> gardenia> rhubarb, on FBG was rhubarb> capillaris> gardenia, and all of the level in medication was better than that in non-medication. There was interaction on FINS,FBG in groups of capillaris and rhubarb, rhubarb and gardenia, interaction on FBG in capillaris and gardenia.
(4) Lipid:The three herb groups could reduce serum TC, gardenia group and rhubarb group could reduce serum TG, LDL-C and TG in liver significantly. Rhubarb group also could increase HDL-C. The degree of the affection by all factors on serum TC, TG, and TG in liver was rhubarb>gardenia> capillaris, all of the level in medication was better than that in non-medication. On LDL-C was rhubarb> gardenia=capillaris, the level of rhubarb and gardenia in medicat ion was better than that in non-medication, the level of capillaris in non-medication was better than that in medication. On HDL-C was rhubarb=capillaris> gardenia, the level of it in rhubarb and capillaris group of medication was better than that of non-medication, the level of it in gardenia group of non-medication was better than that of medication. There was interaction on serum TC, TG, LDL-C and TG in liver in all combination groups.
(5) Antioxidant and lipid peroxidation:The level of serum and liver MDA was lower significantly in the three herb groups. The degree of the affection by all factors on serum MDA was rhubarb>capillaris>gardenia, on liver MDA was capillaris>rhubarb>gardenia, all of the level in medicat ion was better than that in non-medication. Gardenia has the weakest affection on MDA among them. There was interaction on serum and liver MDA in all combination groups. The level of serum GSH-PX was increased significantly in the three herb groups. Also the level of it in liver was increased in capillaris and gardenia gourp. The degree of the affection by all factors on serum GSH-PX was gardenia>rhubarb>capillaris, all of the level in medication was better than that in non-medication. On liver GSH-PX was gardenia> capillaris>rhubarb, the level of it in gardenia and capillar is group of medicat ion was better than that of non-medicat ion, the level of it in rhubarb group of non-medication was better than that of medication. Gardenia has the greatest impact on GSH-PX among them. There was interaction on serum GSH-PX in capillaris and gardenia gourp, capillaris and rhubarb group.Also the interaction on liver GSH-PX in capillaris and rhubarb group.
(6) Inflammation:The level of serum TNF-a was lower significantly in the three herb groups, the express ion levels of TNF-a in liver was lower in rhubarb group and gardenia gourp. The degree of the affection by all factors on serum TNF-a was gardenia=rhubarb>capillaris, all of the level in medication was better than that in non-medication. On TNF-a in liver was gardenia> rhubarb> capillaris. Gardenia had the greatest impact on TNF-a of all, and capillaris had the minimal impact. There was interaction on serum TNF-a in all combination groups. Also the interaction on liver TNF-a in capillaris and gardenia group.
Conclusion
(1) Rhubarb, capillaris and gardenia used alone had a significant effect on NASH,which role was similar but different emphases and had complementary also.The three herbs could treat NASH by regulating liver function, promoting lipid metabolism, inhibiting lipid peroxidation and inflammation, enhancing the antioxidant capacity. The efficacy of rhubarb on protecting the liver and regulating lipid was the best. On enhancing the antioxidant capacity, both capillaris and gardenia was better than rhubarb. Rhubarb, capillaris and gardenia has complementary in regulating model glucose and insulin levels. Rhubarb may has a more comprehensive treatment than capillaris and gardenia.
(2) The three combinations of the herbs had interaction and complementary in many aspects of NASH. All of the them could affect liver function, lipid metabolism, lipid peroxidation and inflammation synergisticly. On enhanc ing the antioxidant capacity of liver, the combination of capillaris and rhubarb was the best. On reducing inflammation of liver, the combination of capillaris and gardenia was the best.
(3) According to the comprehensive analysis of the results of the study, we could speculate that efficacy of YCHD may be not better than rhubarb on lipid-lower ing. Whi le on hepatoprotect ive, anti-inf lamination, inhibi t ion of lipid peroxidation and regulation of blood sugar and insulin, the whole prescription may be better than other single herbs or combinations. Whether the regulatory role of the antioxidant capacity in liver is better than each combination or not need to be confirmed.
(4) The routine dose of YCHD used in clinical may be higher, safer and more effective than high-low dose. Demonstrated better efficacy trends of the traditional decoct ion compared wi th recipe granular formulat ions in the present s tudv.
1文献综述
通过近10年的国内外文献资料分析,探讨归纳了NASH现代医学的病因、发病机制、治疗研究近况及中医学的NASH病因病机、体质学、证候学、治疗研究的进展情况。
2茵陈蒿汤对MCD小鼠模型NASH的研究
目的
探讨茵陈蒿汤治疗MCD小鼠模型NASH的疗效。
方法
MCD饲料喂养雄性C56BL/6小鼠2周建立NASH小鼠模型,造模成功后,各治疗组分别给予茵陈蒿汤高、中(临床常规剂量)、低剂量灌胃干预2周,空白组和模型组给予蒸馏水干预,治疗结束后处死各组小鼠,观察各组小鼠的肝组织病理学改变,检测肝功能、血脂、肝组织SOD、GSH-PX活性、MDA及肝脂含量。
结果
(1)一般情况及病理形态学：模型组小鼠较空白组NAS病理评分显著升高,体重降低、肝指数升高；茵陈蒿汤高、中剂量组能显著降低模型的肝指数,各剂量组均能明显降低模型组脂肪变性、小叶内炎症、气球样变评分。
(2)肝脏酶学：模型组小鼠肝酶学水平较空白组显著升高,茵陈蒿汤中剂量组能显著降低小鼠ALT水平,茵陈蒿汤高、低剂量组对肝酶学水平无显著影响。
(3)血脂及肝脂：模型组血清TC、TG、HDL-C含量较窄白组降低,LDL-C、肝TG含量显著升高,茵陈蒿汤高、中剂量组能显著降低血清TC,TG, LDL-C、及肝TG含量；低剂量组能显著降低TC、LDL-C及肝TG含量,各剂量组对HDL-C水平无显著影响。
(4)抗氧化及改善脂质过氧化：模型组肝组织GSH-PX、SOD含量较空白组显著降低,MDA升高；各剂量组均能降低模型肝内MDA含量,对肝内SOD、GSH-PX水平无显著影响。
结论
茵陈蒿汤配方颗粒剂型临床常规剂量能显著改善MCD小鼠NASH模型的肝组织病理、改善肝细胞脂肪变性,通过促进小鼠模型的肝脂血脂代谢、抑制脂质过氧化反应,减轻肝细胞损伤而降低ALT,对增强抗氧化能力作用不显著。茵陈蒿汤的临床常规剂量疗效优于高剂量,高剂量又优于低剂量。
3茵陈蒿汤对HFD大鼠模型NASH的研究
目的
探讨茵陈蒿汤治疗HFD大鼠模型NASH的疗效及对胰岛素抵抗的调控作用。
方法
高脂饲料喂养SD雄性大鼠8周建立NASH大鼠模型,造模成功后,各治疗组分别给予茵陈蒿汤高、低剂量(临床常规剂量)及复方益肝灵灌胃治疗4周,自然恢复组予基础饲料。治疗结束后所有大鼠取材,观察各组大鼠的肝组织病理学改变,检测肝功能、血脂、肝脂、血糖、血清胰岛素含量及抗氧化指标,计算HOMA-IR,RT-PCR法检测肝组织DGAT-2、PKC-ε、IRS-1、TNF-α mRNA的表达水平。
结果
(1)病理：茵陈蒿汤低剂量组和自然恢复组能显著、全面改善模型肝组织脂肪变性、气球样变及炎症的病理表现,茵陈蒿汤高剂量组、复方益肝灵组能显著改善炎症及气球样变,降低NAS评分,而对脂肪变性的评分降低不显著。
(2)肝脏酶学：茵陈蒿汤高剂量组显著升高模型ALT、AST水平,复方益肝灵组显著升高AST水平,而茵陈蒿汤低剂量组能一定程度降低ALT、AST水平,自然恢复组对ALT、AST无显著调节作用。
(3)血脂及肝脂：复方益肝灵组、茵陈蒿汤低剂量组均能显著降低血清TC、TG. LDL-C水平,高剂量组能降低血清TG含量,自然恢复组能降低血清TG,LDL-C含量,但三个药物治疗组对HDL-C的水平均无显著影响,自然恢复组对升高HDL-C水平具有显著调节。茵陈蒿汤低剂量组及自然恢复组能显著降低模型肝组织FFA、DAG、TG含量,茵陈蒿汤高剂量组、复方益肝灵组能显著减少肝组织FFA、DAG含量,对降低TG作用不显著。茵陈蒿汤低剂量在调节脂质代谢方面的疗效优于高剂量与复方益肝灵片,在调节血脂方面,复方益肝灵片优于高剂量,而在调节肝脂方面,两者作用相当。
(4)血糖、胰岛素及外周胰岛素抵抗：茵陈蒿汤高、低剂量组及复方益肝灵组能显著降低FBG、FINS含量及HOMA-IR,各组间无显著差异。自然恢复组FINS水平及HOMA-IR有下调趋势,FBG水平升高有升高趋势,但无显著意义。
(5)抗氧化及改善脂质过氧化：茵陈蒿汤低剂量组能显著降低血清、肝脏MDA含量,升高血清GSH-PX水平,高剂量组能显著降低血清MDA含量,升高血清GSH-PX水平,茵陈蒿汤两个剂量组对肝内GSH-PX含量无显著影响。复方益肝灵组能显著降低血清及肝内MDA含量,对血清及肝脏GSH-PX有升高趋势,但无显著差异。自然恢复组既能显著降低血清、肝内MDA含量,也能升高血清、肝内GSH-PX水平,各组对血清及肝内SOD水平均无显著影响。茵陈蒿汤低剂量对脂质过氧化的整体作用优于高剂量。在增强外周抗氧化能力方面,茵陈蒿汤优于复方益肝灵片,在增强肝脏抗氧化能力方面,复方益肝灵片对模型虽无显著改善,但其作用优于茵陈蒿汤。
(6)肝脏胰岛素抵抗及炎症：茵陈蒿汤低剂量组能显著降低)GAT-2、PKC-ε、TNF-a mRNA表达水平,升高IRS-1mRNA表达水平,高剂量组及复方益肝灵组能显著降低PKC-ε、TNF-α mRNA表达水平,升高IRS-1mRNA表达水平,对DGAT-2表达有抑制作用,但无显著意义。
结论
(1)茵陈蒿汤能够针对NASH发病的“二次打击”机制起效。针对第一次打击的IR和脂质代谢紊乱环节,减少肝内积聚的过量脂质,促进血脂代谢,改善肝细胞脂肪变性状态,并调节血糖、胰岛素的分泌利用,改善外周IR。针对第二次打击氧应激和脂质过氧化的环节,增强外周抗氧化能力、清除自由基代谢产物,抑制脂质过氧化和炎症反应,恢复氧化系统的失衡状态。茵陈蒿汤常规剂量的作用优于高剂量。在减轻肝脂积聚、增强外周抗氧化能力方面,常规剂量优于复方益肝灵片,复方益肝灵片在增强肝脏抗氧化能力方面优于茵陈蒿汤常规剂量。
(2)茵陈蒿汤高剂量可能由于过量使用对模型肝脏存在一定的毒副作用,复方益肝灵片也对模型肝脏产生了一定的毒副作用,但其具体原因尚不能定论。高剂量与复方益肝灵片作用相当,复方益肝灵片在增强肝脏抗氧化能力方面优于茵陈蒿汤高剂量。
(3)茵陈蒿汤调控NASH大鼠模型肝脏IR的作用机制,部分可能为通过作用于DAG-PKCε信号通路异常的相关因子和炎症因子起效。
(4)模型大鼠在无药物干预的情况下,在血脂、肝脂代谢、脂质过氧化程度的改善和外周抗氧化能力增强方面恢复较好,而在肝细胞的修复、葡萄糖的摄取利用、胰岛素的分泌调节方面短期不能自行恢复而需药物干预。
4茵陈蒿汤拆方对HFD大鼠模型的正交研究
目的
从拆方的角度出发研究茵陈蒿汤对NASH的作用机制,探讨方中各药物及组合对NASH的作用疗效差异,以认识各药物与NASH的相关性,明确药物间的组合是否具有交互作用。
方法
采用正交设计法,对茵陈蒿汤的组成药物进行3因素、2水平的交互研究,运用正交表L8(2’)将大鼠分为8组,高脂饲料喂养SD雄性大鼠8周建立NASH大鼠模型,造模成功后,各治疗组分别给予茵陈、栀子、大黄、茵陈栀子、茵陈大黄、栀子大黄、茵陈蒿汤灌胃治疗4周,治疗结束后所有大鼠取材,观察各组大鼠的肝组织病理学改变,检测肝功能、血脂、肝脂、血糖、血清胰岛素含量及抗氧化指标,RT-PCR法检测肝组织TNF-α mRNA的表达水平。
结果
(1)一般情况及病理形态学：模型组NAS病理评分、体重、肝指数较空白组明显升高；栀黄组体重、茵陈蒿汤组肝指数有降低趋势,但无显著差异,其余各治疗组体重及肝指数均有显著降低；各治疗组脂肪变性、小叶内炎症、气球样变评分均显著下降,各治疗组之间无显著差异。
(2)肝脏酶学：大黄组、茵陈组、栀子组能显著降低ALT水平(P=0.043,0.047,0.042)；大黄组能显著降低AST水平(P=0.039),茵陈组、栀子组作用不显著(P=0.054,0.088)。对三种药物各自用药与不用药时的疗效差异进行比较,各因素对ALT的效应程度为栀子>大黄>茵陈,对AST为茵陈>大黄>栀子,且均以用药水平为优；茵黄组对ALT、AST存在交互作用(P=0.039,0.024),栀黄组、茵栀组对AST存在交互作用(P=0.021,0.046),对ALT不存在交互作用(P=0.057,0.055)。
(3)血糖、胰岛素：大黄组、茵陈组能显著降低FINS水平(P=0.032,0.049),栀子组作用不显著(P=0.213)；大黄组、茵陈组能显著降低FBG水平(P=0.049,0.040),栀子组作用不显著(P=0.075)。各因素对FINS的效应程度为茵陈>栀子>大黄,对FBG为大黄>茵陈>栀子,均以用药水平为优；茵黄组、栀黄组对FINS(P=0.011,0.023)、FBG存在交互作用(P=0.018,0.046),茵栀组对FBG存在交互作用(P=0.031),对FINS不存在交互作用(P=0.134)。
(4)血脂及肝脂：大黄组、茵陈组、栀子组能显著降低TC水平(P=0.020,0.022,0.020)；大黄组、栀子组能显著降低血清TG(P=0.044,0.039)、LDL-C(P=0.042,0.013)、肝组织TG(P=0.012,0.035)含量,茵陈组作用不显著(P=0.288,0.156,0.110)；大黄组能显著升高HDL-C水平(P=0.045),茵陈组、栀子组作用不显著(P=0.056,0.081)；各因素对血清TG、TC、肝脏TG的效应程度均为大黄>栀子>茵陈,均以用药水平为优；对LDL-C为栀子>大黄=茵陈,栀子、大黄以用药水平为优,茵陈以不用药水平为优；对HDL-C为大黄=茵陈>栀子,大黄、茵陈以用药水平为优,栀子以不用药水平为优；茵黄组、栀黄组、茵栀组对血清TC(P=0.021,0.045,0.021)、TG(P=0.045,0.025,0.026)、LDL-C(P=0.002,0.003,0.002)、肝组织TG(P=0.016,0.027,0.037)存在交互作用,对HDL-C不存在交互作用(P=0.063,0.058,0.157)。
(5)抗氧化及改善脂质过氧化：大黄组、茵陈组、栀子组能显著降低血清MDA(P=0.009,0.01,0.006)及肝组织MDA含量(P=0.008,0.009,0.013),各因素对血清MDA的效应程度为大黄>茵陈>栀子,对肝组织MDA为茵陈>大黄>栀子,均以用药水平为优,三者以栀子对MDA含量影响效应程度最小；茵黄组、栀黄组、茵栀组对血清MDA(P=0.047,0.008,0.005)及肝组织MDA(P=0.016,0.006,0.047)存在交互作用；大黄组、茵陈组、栀子组能显著升高血清GSH-PX水平(P=0.017,0.014,0.009),茵陈组、栀子组能显著升高肝组织GSH-PX含量(P=0.034,0.014),大黄组作用不显著(P=0.052),各因素对血清GSH-PX的效应程度为栀子>大黄>茵陈,均以用药水平为优；对肝组织GSH-PX为栀子>茵陈>大黄,栀子、茵陈以用药水平为优,大黄以不用药水平为优,三者中以栀子对GSH-PX含量的影响程度最大；茵黄组、茵栀组对血清GSH-PX存在交互作用(P=0.045,0.008),栀黄组不存在交互作用(P=0.101)；茵黄组对肝组织GSH-PX存在交互作用(P=0.029),茵栀组、栀黄组不存在交互作用(P=0.063,0.072)。
(6)炎症：大黄组、茵陈组、栀子组能显著降低血清TNF-α水平(P=0.021,0.048,0.014),大黄组、栀子组能显著降低肝组织TNF-α mRNA表达水平(P=0.049,0.036),茵陈组作用不显著(P=0.100),各因素对血清TNF-α的效应程度为栀子=大黄>茵陈,对TNF-α mRNA为栀子>大黄>茵陈,均以用药水平为优,三者以栀子对TNF-α影响程度最大,茵陈最小；茵黄组、栀黄组、茵栀组对血清TNF-α存在交互作用(P=0.048,0.022,0.011),茵栀组对肝组织TNF-a mRNA表达具交互作用(P=0.040),茵黄组、栀黄组未见交互(P=0.066,0.322)。
结论
(1)大黄、茵陈、栀子单独使用时对大鼠NASH模型的脂代谢紊乱、胰岛素效应降低、脂质过氧化、炎症等方面即存在显著疗效,其作用多有相似又各有侧重,药物间的作用对治疗NASH具有互补性,大黄保肝降酶及调节血脂的作用最佳,茵陈与栀子对增强机体抗氧化能力的作用优于大黄,大黄、茵陈与栀子在调节模型血糖、胰岛素水平方面的作用具有互补性。大黄较茵陈、栀子对该模型可能具有更全面的治疗作用。
(2)三种药物的组合对NASH的多个方面具有协同交互作用,各组合间的作用对治疗NASH具有互补性,茵陈与大黄能协同增强模型的肝脏抗氧化能力,优于其他组合；茵陈与栀子能协同抑制模型肝脏炎症,优于其他组合；栀子与大黄在增强机体抗氧化能力方面无显著交互作用。
(3)根据上述研究结果综合分析,推测茵陈蒿汤全方对HFD大鼠NASH模型在降脂方面作用可能不及大黄,在保肝、抑炎、抑制脂质过氧化调节血糖与胰岛素的水平方面,可能较其他单药或组合更佳,对肝脏抗氧化能力的调节作用是否优于各组合尚需研究证实。
(4)茵陈蒿汤在临床中使用的常规剂量可能较高、低剂量更为安全有效,本研究中,传统水煎剂较配方颗粒剂型表现出更佳的疗效趋势。
Comprehensive learning of non-alcoholic steatohepatitis(NASH) in both modern medicine and traditional chinese medicine (TCM)is demonstrated through literature review,and animal experimental study in this paper. Efficacy and mechanism of Yinchenhao Decoction is explored in the animal experimental study.The research provided a basis to further reveal the mechanism of Yinchenhao Decoction and to explore new Cuban side to enhance by the side of the value of academic research in the field and clinical therapeutic levels.
1Literature review
Through literature analysis in recent10years both at home and abroad, the etiology,pathogenesis,and treatment of modern medicine, also etiology and pathogenesis, syndrome differentiation, physical sciencetreatment progress of TCM have been review.
2Effects of Yinchenhao Decoction on mice with NASH on MCD diet
Objective
To investigate the efficacy of Yinchenhao Decoction(YCHD) on mice with non-alcoholic steatohepatitis (NASH) on MCD diet.
Method
The C57BL/6mice was fed with MCD diet for2weeks to make NASH mice model. After modeling, the treatment group were intervened by YCHD high, middle (conventional dosage), low dose for4weeks. Then the change of serum transaminase, serum lipid, liver lipid, Lipid peroxidation indexes and the liver pathology had been detected to observe the efficacy.
Outcome
(1) General condition and pathomorphology:The hepatic steatosis and inflammation,also liver index were increased, body weight was reduced in model group, but improved in the treatment group compared with model group. NAS score was reduced significantly at the same time.And there was no significant difference between the all treatment group. Liver index was reduced significantly in the high and middle dose groups of YCHD group.
(2) Serum transaminase:Compared with blank control group, the serum ALT, AST in model group were obviously increased. The serum ALT decreased in YCHD middle dose group, and there was no signicficant difference in improving liver function them. The indexes had no signicf icant change in high and low dose groups of YCHD.
(3) Lipid:Serum TC, TG, HDL-C was reduced, LDL-C and TG in liver was increased in the model compared with blank control group. The high and middle dose groups of YCHD could decrease serum TC, TG, LDL and liver TG significantly, the low dose of YCHD could decrease serum TC, LDL and liver TG. There was no signicficant change in serum HDL of all groups.
(4) Lipid peroxidation indexes:In model group, the MDA content in liver were increased, the GSH-PX and SOD was decreased compared with the blank control group. In treatment groups, the MDA were decreased significantly. As the GSH-PX and SOD, there was no significant difference among all groups.
Conclusion
The three dose of YCHD could improve the liver pathological change, decrease liver lipid and MDA level significantly. The high and middle dose was good at reducing liver index and blood lipid, which was better than the low dose at blood lipid. Only the middle dose could reduce the serum ALT. Overall, the efficacy of conventional dose was the best among them, and the high dose is better than the low.
3Research of efficacy and therapeutic mechanism of YCHD to NASH for rat fed on high fat diet
Objective
To investigate the efficacy and therapeutic mechanism on regulating insulin resistance of YCHD on rat with NASH on high fat diet.
Methods
NASH model in SD rats was established by feeding high fat diet for8weeks, After modeling, the treatment and control group were intervened by YCHD high, low(conventional dose) dose and compound yiganling for4weeks, natural recovery group was restored to normal diet. Then the change of serum transaminase, serum lipid,fas ting blood glucose, fasting insulin,liver lipid, lipid peroxidation indexes,the liver pathology and expression levels of DGAT-2、PKC-ε、INS-1、TNF-α、mRNA of the liver had been detected to observe the efficacy and mechanism.
Outcome
(1) Pathomorphology change:After treatment, the steatosis, lobular inflammation, ballooning and total scores all decreased by the low dose of YCHD and natural recovery group s ignif icant ly. The high dose of YCHD and control group improved the lobular inflammation and ballooning.
(2) Serum transaminase:The serum transaminase was increased in YCHD high dose group,and the serum AST increased in control group. The low dose of YCHD reduced the serum transaminase but there was no signicficant change.
(3) Lipid:Serum TC, TG, LDL-C was reduced in the low dose of YCHD and control group, TG reduced in the high dose, TG reduced in the natural recovery group. There was no signicficant change on HDL-C in the treatment groups,while increased in the natural recovery group. ALL groups could reduced FFA contents in the liver and there was no signicficant difference between them, the low dose of YCHD could decrease DAG, TG contents in the liver, the high dose and compound yiganling decrease DAG signicficantly.
(4) FBG,FINS and peripheral insulin resistance:The level of FBG and FINS in serum of all treatment groups were significantly lower than those of model group. There was no significant difference among them. ALL groups could reduce the level of HOMA-IR, but there was no significant change.
(5) Lipid peroxidation indexes:The activities of serum GSH-PX and level of serum and1iver MDA were significantly improved in the low dose of YCHD, which was better than that of the high dose and compound yiganling group. GSH-PX in liver had no significant change in all treatment groups. While the natural recovery group could increase GSH-PX in liver also the other lipid peroxidation indexes. There was no significant change on SOD in all groups.
(6) Hepatic insulin resistance and inflammation:The expression of PKC-5and TNF-a in liver was significantly reduced, the expression of IRS-1was increased in all treatment groups.There was no significant difference among them. Meanwhile, the low dose of YCHD could also reduce the expression of Dgat-2in liver, but the level of it had no signif icant change in high dose and yiganling group.
Conclusion
(1) YCHD has good efficacy on NASH rats feeding by high fat diet with pathogenesis of "two-hit" mechanism by improving the steatosis, disorders of glucose and lipid metabolisin, also peripheral insulin resistance. Enhancing antioxidant ability and clearing free radical metabolites to inhibit lipid peroxidation. YCHD conventional dose is better than high dose on rats NASH model. On enhancing the periphery antioxidant capacity and alleviating liver fat accumulation, YCHD conventional dose was better than compound yiganling piece. On enhancing liver antioxidant capacity, compound yiganling tablets was better than YCHD conventional dose.
(2) There might be certain side effects due to excessive use of high dose. The compound yiganling sheet had certain side effects also, but the specific cause could not yet be conclusive. The high dose was quite to compound yiganling piece. On enhancing liver antioxidant capacity, compound yiganling tablets was better than YCHD high dose.
(3) By regulating the related factors and inflammatory factors on signaling pathway of DAG-PKC ε, YCHD could improve he patic insulin resistance. This is part of the mechanism of the regulation of insulin resistance by YCHD.
(4) Rat model in the case of non-pharmacological interventions, had better recovery in blood lipids, liver lipid metabolism, lipid peroxidation degree and the outer periphery of antioxidant capacity, but could not restore itself without a drug intervention in repairing liver cells, uptake and utilization of glucose, regulation of insulin secretion in short-term.
4Research of interaction by disassembling YCHD to NASH for rat fed on high fat diet by orthogonal design
To observe the difference of efficacy of each herb and combinations in YCHD on NASH for the correlation between drugs and NASH, interaction between drugs.
Method
Methods of orthogonal design and disassembling the prescription was taken in this study, three factors and two level are confirmed, according to orthogonal layout L8(2'), rats were divided into8groups and were intervened by corresponding herb and combination for4weeks to observe the pathological changes of hepatic tissue, serum transaminase, serum lipid, fasting blood glucose, fasting insulin,liver lipid, lipid peroxidation indexes, and expression levels of TNF-a in liver.
Outcome
(1) General condition and pathomorphology change:The NAS score, body weight and liver index were increased in model group. Except body weight of YCHD, and liver index of gardenia and rhubarb group,NAS score of steatosis, lobular inflammation, ballooning in other treatment groups was reduced significantly. There was no significant difference among all treatment groups.
(2) Serum transaminase:The level of serum ALT was reduced in gardenia, rhubarb and capllaris group, of serum AST was reduced in rhubarb group significantly. When medication and non-medication, the degree of the affection by all factors on ALT is gardenia> rhubarb>capi1laris, on AST was capillaris>rhubarb>gardenia, and all of the level in medica t ion was better than that in non-medication.There was interaction on ALT, AST in group of capillaris and rhubarb, interaction on AST in rhubarb and gardenia, capillar is and gardenia.
(3) FBG and FINS:Rhubarb group and capillar is group could reduce the level of FINS and FBG significantly. The degree of the affection by all factors on FINS was capillaris> gardenia> rhubarb, on FBG was rhubarb> capillaris> gardenia, and all of the level in medication was better than that in non-medication. There was interaction on FINS,FBG in groups of capillaris and rhubarb, rhubarb and gardenia, interaction on FBG in capillaris and gardenia.
(4) Lipid:The three herb groups could reduce serum TC, gardenia group and rhubarb group could reduce serum TG, LDL-C and TG in liver significantly. Rhubarb group also could increase HDL-C. The degree of the affection by all factors on serum TC, TG, and TG in liver was rhubarb>gardenia> capillaris, all of the level in medication was better than that in non-medication. On LDL-C was rhubarb> gardenia=capillaris, the level of rhubarb and gardenia in medicat ion was better than that in non-medication, the level of capillaris in non-medication was better than that in medication. On HDL-C was rhubarb=capillaris> gardenia, the level of it in rhubarb and capillaris group of medication was better than that of non-medication, the level of it in gardenia group of non-medication was better than that of medication. There was interaction on serum TC, TG, LDL-C and TG in liver in all combination groups.
(5) Antioxidant and lipid peroxidation:The level of serum and liver MDA was lower significantly in the three herb groups. The degree of the affection by all factors on serum MDA was rhubarb>capillaris>gardenia, on liver MDA was capillaris>rhubarb>gardenia, all of the level in medicat ion was better than that in non-medication. Gardenia has the weakest affection on MDA among them. There was interaction on serum and liver MDA in all combination groups. The level of serum GSH-PX was increased significantly in the three herb groups. Also the level of it in liver was increased in capillaris and gardenia gourp. The degree of the affection by all factors on serum GSH-PX was gardenia>rhubarb>capillaris, all of the level in medication was better than that in non-medication. On liver GSH-PX was gardenia> capillaris>rhubarb, the level of it in gardenia and capillar is group of medicat ion was better than that of non-medicat ion, the level of it in rhubarb group of non-medication was better than that of medication. Gardenia has the greatest impact on GSH-PX among them. There was interaction on serum GSH-PX in capillaris and gardenia gourp, capillaris and rhubarb group.Also the interaction on liver GSH-PX in capillaris and rhubarb group.
(6) Inflammation:The level of serum TNF-a was lower significantly in the three herb groups, the express ion levels of TNF-a in liver was lower in rhubarb group and gardenia gourp. The degree of the affection by all factors on serum TNF-a was gardenia=rhubarb>capillaris, all of the level in medication was better than that in non-medication. On TNF-a in liver was gardenia> rhubarb> capillaris. Gardenia had the greatest impact on TNF-a of all, and capillaris had the minimal impact. There was interaction on serum TNF-a in all combination groups. Also the interaction on liver TNF-a in capillaris and gardenia group.
Conclusion
(1) Rhubarb, capillaris and gardenia used alone had a significant effect on NASH,which role was similar but different emphases and had complementary also.The three herbs could treat NASH by regulating liver function, promoting lipid metabolism, inhibiting lipid peroxidation and inflammation, enhancing the antioxidant capacity. The efficacy of rhubarb on protecting the liver and regulating lipid was the best. On enhancing the antioxidant capacity, both capillaris and gardenia was better than rhubarb. Rhubarb, capillaris and gardenia has complementary in regulating model glucose and insulin levels. Rhubarb may has a more comprehensive treatment than capillaris and gardenia.
(2) The three combinations of the herbs had interaction and complementary in many aspects of NASH. All of the them could affect liver function, lipid metabolism, lipid peroxidation and inflammation synergisticly. On enhanc ing the antioxidant capacity of liver, the combination of capillaris and rhubarb was the best. On reducing inflammation of liver, the combination of capillaris and gardenia was the best.
(3) According to the comprehensive analysis of the results of the study, we could speculate that efficacy of YCHD may be not better than rhubarb on lipid-lower ing. Whi le on hepatoprotect ive, anti-inf lamination, inhibi t ion of lipid peroxidation and regulation of blood sugar and insulin, the whole prescription may be better than other single herbs or combinations. Whether the regulatory role of the antioxidant capacity in liver is better than each combination or not need to be confirmed.
(4) The routine dose of YCHD used in clinical may be higher, safer and more effective than high-low dose. Demonstrated better efficacy trends of the traditional decoct ion compared wi th recipe granular formulat ions in the present s tudv.
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